Long term follow-up results of IFM99-03
and IFM99
IFM99-04 comparing non
myeloablative allotransplantation with
autl
tologous transplantt
ta i
tion in hi
high ik
-risk de
novo multiple myeloma
P.Moreau, F.Garban, M.Attal, M.Michallet, G.Marit, C.Hulin,
L B
. enboubker
Benboubker, C Doyen
.
, M Mohty
.
, I Yakoub
.
-Agha, S.Leyvraz
Leyvraz, P.Casassus
Casassus,
H.Avet-Losieau, L.Garderet, C.Mathiot, J.L.Harousseau
Overall survival according to the number of unfavorable
prognostic factors (High beta-2 mic, del 13)
Survival
10
1.0
0.8
# factors
O/N
Survival time
(month)
0.6
0
2/22
> 111.
1
29/55
47.3 ± 46
4.6
0.4
2
22/33
25.3 ± 3.2
0.2
P < .0001
0.0
0
12
2436
4860
728496
time from diagnosis (months)
Facon et al , Blood 2001
STUDY DESIGN
High-risk de novo MM, < 65 years
beta2-mic > 3 & del 13
13
Enrollment : 284 (from 04/2000 to 08/2004)
IFM 9903 : 65
IFM9904 : 219
(23%)
(77%)
Enrollment IFM 9903 or 9904 : 284
FLOW CHART
CHAR
IFM 9903 : 65
IFM9904 : 219
VAD
Progr
Pr
ession
ogr
Infection
HDM200
Death
Rf
Refusal
Violation
Feasibility : 76%
Randomisation
53 (24%)
166
Arm A : HDM220
Arm B : HDM220+anti-IL6moAb
85
81
Arm A
Arm B
p
n = 85
n = 81
Age at diagnosis
56 (34-65)
58 (28-65)
0.053
Sex (M/F)
41 / 44
47 / 34
0.28
Isotype
yp (G/A/BJ)
45/23/17
42/24/15
0.93
Stage (I/II/III)
1/9/75
0/10/71
0.98
Beta2mic
4.6 (3-28.5)
4.8 (3-37.2)
0.35
Albumin
95(
9.5 5
(5 1
. -14 7)
.
10 2
. (4
(4 7
. -14 4)
.
01
0. 4
14
Platelets
216 (60-462)
204 (84-469)
0.63
Hb
38 (22.5-54)
37 (16.2-52)
0.62
Ca
2.42 (1.96-4.5)
2.42 (1.87-4.03)
0.85
CRP
7 (1-244)
5 (1-137)
0.22
Moreau et al, Blood 2006
1.0
0.9
Event-
Event free
fr
survival
0.8
Arm A
0.7
Arm B
0.6
0.5
ival
0.4
Surv
of
p = .39
0.3
babilityo
0.2
Pr
0.1
0
0
12
2436
4860 months
Moreau et al, Blood 2006
1.0
Overall survival
0.9
Arm A
0.8
Arm B
07
0.7
0.6
0.5
alv
Survi
0.4
of
p = .90
0.3
bability
Pro
0.2
0.1
0
0
122436
48
60
months
Moreau et al . Blood 2006
Cl
Concl
i
us on: IFM99
IFM99 04
-
The addition of anti-IL6 moAb (+ mel 220)
does not improve the outcome of high-risk
patients
IFM99-03
First ASCT : HDM200
RIC :
- Busulphan : 2 mg/kg/d, 2 days
- Fludarabine : 25 mg/kg/d, 5 days
- ATG, Imtix, Genzyme : 2.5 mg
yg/kg/d, 5 days,
days ­5 -1
- allogeneic PBSC day 0
IFM99-03
GVHd prophylaxis :
CyA 3 mg/kg/d, day ­1 day 100
Sh
t
or -course
th
me otrexate
Day 90 : additional DLI if incomplete chimerism or
persistent disease
65 patients included
19 did not
not complete :
- Progressive disease
disease : 7
- Donor refusal : 2
- Recipient refusal : 3
- Ongoing infection : 4
- Other : 3
46 patients (71%) completed the entire
program
GVHd :
Acute : 15/46 (32%),
grade I in 4, grade II-IV in 11 (24%)
Chronic : 42
42 evaluable
evaluable
3 limited (7.1%) and 15 (36%) extensive (5 after
DLI)
TRM :
Low !! 5/46 (11%)
2 b f
e ore day 100 : viral pneumonitis, septi
ticemia
3 after
after day
day 100 : infections
infections related to GVHd
DLI : 17 patients
8 persistent disease without GVHd at day 90,
stt
tar i
ting dose : 1 x 10
107 CD3+/kg, 2 t
p s
d
secon DLI 5 x
107, and 1 pt third 108/kg
5 responses
(CR or VGPR)
9 later, at the time of relapse, no response
!! Not systemati
ti
l
ca l
lly used
Comparison 03 vs 04
IFM 99-03
IFM 99-04
n = 65
n = 219
p
!! Chromosome 13 del
100%
100%
!! Beta2-mic >3
100%
100%
Age at diagnosis
54 (36-65)
58 (28-65)
.006
Sex (M/F)
32 / 33
114 / 105
.79
Isotype (G/A/BJ)
35 / 21
21 / 9
121 / 62
62 / 36
64
.
Stage (I/II/III)
1 / 10 / 54
2 / 24 / 193
.85
Beta2-mic (mg/L)
4.1 (3.1-16.6)
4.9 (3.03-39.4)
.049
Albumin (g/L)
38 (27-52)
38 (16.2-54)
.47
Platelets (G/L)
220 (45-346)
211 (20-500)
.65
Hb (g/dL)
9.8 (5.2-13.5)
9.8 (4.7-14.7)
.82
Ca (mM/L)
2.4 (1.8-3.97)
2.43 (1.87-4.5)
.41
CRP (mg/L)
5(
5 1
(1-132)
6(
6 1
(1-279)
48
.
Moreau et al, Blood 2008
1.0
0.9
Median follow-up: 56 months
0.8
22 vs 19 months, p = 58
.
0.7
al 0.6
ivrvu
S 0.5
of
0.4
Probability
0.3
0.2
IFM99-03, 65 patients
0.1
IFM99-04, 219 patients
0
0
600
1200
1800
2400
3000
Et
Event fi
-free survival, i t
n
t
en t
-
tt
o-treat
1.0
Median follow-up: 56 months
0.9
Median follow-up: 56
0.9
48 vs 34 months,p
months,
months p = .07
0.8
0.7
06
0.
0 6
0.5
IFM99-04, 219 patients
0.4
0.3
0.2
IFM99-03, 65 patients
0.1
0 0
600
1200
1800
2400
3000
days
ay
Overall survival,
survival intent-to-treat
tr
1.0
0.9
Median follow-up: 56 months
0.8
25 vs 21
th
mon s, p = .88
0.7
0.6
0.5
aliv
Surv
0.4
of
babilityo
Pr
0.3
IFM99-03, 46 patients
0.2
0.1
IFM99 04
-
, 166 patients
0
0
600
1200
1800
2400
3000
EFS, treatment completed
1.0
Median follow
follow up:
-
56 months
0.9
57 vs 41 months, p = .08
0.8
0.7
0.6
IFM99-04, 166 patients
0.5
alvi
Surv
of
0.4
ty
Probabili
0.3
IFM99 03
-
, 46
ti
pa
t
en s
0.2
0.1
0
0
600
1200
1800
2400
3000
OS, treatment
tr
completed
DISCUSSION
Auto/miniallo in frontline treatment of multiple myeloma
< 65 years : controversial issue
« good results » with ASCT + novel agents
« good
g
results » auto/miniallo vs tandem tranplant
p
Bruno et al, N Engl J Med 2007
(Rosinol et al, Blood 2008)
This can be explained through the different study design.
high-risk disease,
i.e. elevated 2 microglobulin
-
plus chromosome 13
abnormalities
conditioning regimen prior to allo-RIC,
busulfan, fludarabin and high-dose
g
ATG, possibl
,p
y
eliminating part of the GVM effect.
Bruno et al, Blood 2008
100 patients, TBI 2 Gy
Gy
median follow-up 5 years
OS
EFS
OS del 13 neg vs pos
EFS del 13 neg vs pos
Bruno et l
a , Bl
Blood 2008
Rotta et al,
Prepublished online Nov 17, 2008
102 patients, TBI 2 Gy (+Fluda)
« ...long-term disease control remains an issue... »
Conclusion
- IFM99-03 vs 99-04, in high-risk patients,
Auto / miniallo < double auto
- Results of 2 recently completed prospective
phase III trials auto/miniallo vs double auto in
Nt
Nor h
th A
i
mer ca
d
an Europe are
l
eager y await
it d
e .